Novel indenothiazole derivative and process for preparing the same

ABSTRACT

This invention provides an indenothiazole derivative and a process for manufacturing the same. The said indenothiazole derivative is represented by the following formula: ##STR1## wherein X and Y are identical with, or different from, each other and are each a hydrogen atom, halogen atom, low alkyl group or low alkoxy group; n is an integer of from 0 to 4; R 1  is a hydrogen atom, low alkyl group, unsubstituted or substituted phenyl group; R 2  is a low alkyl group, cycloalkyl group, low alkoxyl group, unsubstituted or substituted phenoxy group, unsubstituted or substituted phenyl group, alkenyl group, heterocyclic group or cycloamino group; R 3  is a hydrogen atom, low alkyl group or acyl group; and R 2  and R 3  may be combined to form a cycloamino group. Further, this invention also provides a tautomer of the compound represented by the above formula (Ia), wherein all the symbols are as defined above except that R 3  is limited to a hydrogen atom.

FIELD OF THE INVENTION

This invention relates to a novel indenothiazole derivative useful as amedicine having an excellent antiulcerative effect, and a process forpreparing the same.

DESCRIPTION OF THE PRIOR ART

With regard to indenothiazole derivative, a process for manufacturing a2-amino indenothiazole derivative is disclosed in Journal of theAmerican Chemical Society, 72, 3722 (1950) and Journal of the ChemicalSociety 2740 (1958). Further, a process for manufacturing a 2-aminoacylindenothiazole derivative and its potential as a medicine for curingallergic diseases are disclosed in Japanese Patent Appln. Laid-OpenGazette No. 58-55474. However, the indenothiazole derivative of thisinvention is neither disclosed nor suggested in any one of the aforesaidpublications. Further, whether its tautomer exists is not known at all.Still further, it was of course unknown whether the indenothiazolederivative has an antiulcerative effect.

The medical treatment of digestive ucler seeks to restrain the attackfactor and strengthen the defense factor. In recent years, in order torestrain the attack factor, a histamine H₂ -antagonist such ascimetidine, ranitidine or famotidine plays the main role as a remedialmedicine for ulcer. Nevertheless, the problem of relapse of ulcerremains unsolved. Further, omeprazole serving as an ATPase inhibitor (ora proton pump inhibitor) restrains acid secretion and has a highselectivity for internal organs. It has a stable effect over a longperiod, but has a problem as to its side effects.

As for reinforcing agents for the defense factor, there are plenty ofmedicines which have the actions of strengthening of mucous membraneresistance, promoting mucus secretion, improving minute circulations andpromoting prostagrandine synthesis. Although these medicines have sominor side effects that they are safely used, they are still notappreciated to be sufficiently effective.

It is an object of this invention to provide a novel indenothiazolederivative, a tautomer thereof or their acid addition salt, which is auseful medicine having an excellent antiulcerative effect with no sideactions.

It is another object to provide a process for preparing the novelindenothiazole derivative, the tautomer thereof or their acid additionsalt.

DISCLOSURE OF THE INVENTION

The novel indenothiazole derivative is represented by the followingformula: ##STR2## wherein X and Y are identical with, or different from,each other and are each a hydrogen atom, halogen atom, lower alkyl groupor lower alkoxy group; n is an integer of 0 to 4; R₁ is a hydrogen atom,lower alkyl group, unsubstituted or substituted phenyl group; R₂ is alower alkyl group, cycloalkyl group, low alkoxy group, unsubstituted orsubstituted phenoxy group, unsubstituted or substituted phenyl group,alkenyl group, heterocyclic group or cyclic amino group; R₃ is ahydrogen atom, lower alkyl group or acyl group; R₂ and R₃ may becombined together to form a cyclic amino group.

Further, the tautomer is represented by the following formula: ##STR3##wherein X, Y, n, R₁ and R₂ are as defined above.

The compounds of the aforesaid formulas (Ia) and (Ib) are describedhereinafter in more detail.

The halogen atom means a fluorine, chlorine, bromine or iodine atom. Thelower alkyl group includes an alkyl group of 1 to 6 carbon atoms such asmethyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert.-butyl,n-pentyl, iso-pentyl or n-hexyl group.

The cycloalkyl group includes a cycloalkyl group having 3 to 7 carbonatoms such as cyclopropyl, cyclopentyl, cyclohexyl or cycloheptyl group.

The lower alkoxy group includes an alcoxy group having 1 to 6 carbonatoms such as methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy,iso-butoxy or tert.-butoxy group.

The substituent in the substituted phenyl or substituted phenoxy groupincludes a halogen atom, lower alkyl group (this group may furthercontain mono- or di-C₁₋₆ alkylamino group as a substituent), hydroxylgroup, lower alkoxy group or trifluoromethyl group.

The alkenyl group includes an alkenyl group having 3 to 6 carbon atomssuch as propenyl, butenyl or butadienyl group.

The heterocyclic group includes 2-pyridyl, 3-pyridyl, 4-pyridyl,2-pyrimidyl, 2-thiazolyl, 2-thiazoline-2-yl or 2-thiazolydinyl group,each of which may be unsubstituted or substituted with the samesubstituent as in the above phenyl or phenoxy group.

The cycloamino group includes a 5- or 6-membered cycloamino group whichmay have nitrogen atoms or oxygen atoms, such as piperidino,pyrrolidino, morpholino, piperazino or pipecolino group. Further, thecycloamino group may be substituted by an alkyl group of 1 to 4 carbonatoms such as methyl or ethyl group, a phenyl-C₁₋₄ alkyl group such asbenzyl group, an alkanoyl group of 2 to 6 carbon atoms such as acetyl orpropionyl group.

The acyl group includes an alkanoyl group of 2 to 6 carbon atoms such asacetyl, propionyl, n-butyroyl or isobutyroyl group, benzoyl group ortrifluoromethylcarbonyl group.

The acid addition salt, which is permissible as a medicine, comprises anacid of equivalent 1 or 2. The suitable acid may for example be aninorganic acid such as hydrochloric, sulfuric, nitric or phosphoric acidas well as an organic acid such as maleic, fumaric, oxalic, succinic,malonic, lactic or citric acid.

In cases where the compounds represented by the aforesaid formulas (Ia)and (Ib) or their acid addition salts are used as a medicine, they maystably be orally or non-orally administered as they are or in the formof tablets, powders, capsules or suppositories prepared using a knownvehicle as well as in the form of injections. The suitable dosage may bedecided in view of a patient's symptoms, age, sex or the like. In caseswhere they are orally dosed as a medicine to cure gastric ulcer,duodenal ulcer or acute or chronic gastritis, it is desirable to dosethe compound represented by the aforesaid formulas (Ia) or (Ib) or itsacid addition salt in an amount of about 1 to 200 mg/kg at a time, aboutonce or three times per day.

The process of manufacturing the compounds of this invention will bedescribed hereinafter. The present compounds may be obtained in a goodyield as indicated by the following embodiments, but this invention isnot limited to them.

The starting or raw materials represented by the following formulas maybe easily synthesized by the known processes disclosed in Journal of theAmerican Chemical Society, 71, 1092 (1949), Journal of the AmericanChemical Society, 75, 640 (1953), Journal Fur Praktische Chemie, 315,144 (1973), Russian Chemical Reviews, 42 (7), 587 (1973), Journal of theChemical Society, 2740 (1958) and so forth. ##STR4## (Wherein X, Y, n,R₁, R₂ and R₃ respectively have the same meaning as previously defined.)

As indicated above, a compound represented by the above formula (II) anda compound represented by the above formula (III) are reacted, for 1 to24 hours at a temperature of 20° to 120° C., in any one of the organicsolvents such as methanol, ethanol, acetone or dimethylformamide, so asto obtain a compound represented by the formula (Ia). Further, thecompound represented by the formula (Ia) in which R₃ is hydrogen atom istreated in an aqueous solution of an acid, so as to obtain its tautomer,i.e. the compound represented by the formula (Ib). ##STR5## (Wherein X,Y, n, R₁, R₂ and R₃ respectively have the same meaning as describedabove; and Hl is a halogen atom.)

First, a compound represented by the formula (IV) is halogenated byreacting with a halogenating agent such as thionyl chloride orphosphorus oxychloride, for 1 to 5 hours at a temperature of 0° to 120°C., in the absence or presence of an aprotic solvent such as benzene ortoluene. Thereafter, the thus obtained halogenated compound is reactedwith an amine represented by the formula (VI) for 1 to 5 hours at atemperature of 20° to 100° C., in the absence or presence of an organicsolvent such as methanol, ethanol or dimethylformamide, thereby toobtain the compound represented by the formula (Ia). Further, it ispossible to obtain the tautomer (Ib) of the compound (Ia) in which R₃ isa hydrogen atom by means of the aforesaid manufacturing process 1.

EXAMPLES

Examples of this invention are described hereinafter, but this inventionis not limited to them.

Example 1

3.5 g of 2-bromo-5-fluoro-1-indanone and 3.1 g ofN-(3-morpholinopropyl)thiourea were added to 40 ml of ethanol. Theresulting mixture was refluxed for 10 minutes, agitated for 24 hours atroom temperature to precipitate crystals which were collected byfiltration. The thus collected crystals were washed with ethanol, dried,incorporated with 40 ml of a 5% aqueous solution of NaOH, extracted withethyl acetate, washed with water, dried, distilled at a reduced pressureand then recrystallized from ethyl acetate-isopropyl ether thereby toobtain 3.9 g of2-(3-morpholinopropyl)amino-6-fluoro-8H-indeno[1.2-d]thiazole. The thusobtained compound had a melting point of 113° to 115° C. and thefollowing analysis.

    ______________________________________                                        Analysis: C.sub.17 H.sub.20 N.sub.3 OFS                                       ______________________________________                                        Calculated   C: 61.24   H: 6.04   N: 12.60                                    Found        C: 61.00   H: 6.04   N: 12.47                                    ______________________________________                                    

Example 2

3.0 g of 2-(3-morpholinopropyl)amino-6-fluoro-8H-indeno[1.2-d]thiazolewere dissolved in 50 ml of 0.1N HCl, allowed to stand for three days atroom temperature, made weakly alkaline with a 5% KOH aqueous solution,extracted with chloroform, water washed, dried, distilled at a reducedpressure to remove the solvent, and then isolated and purified by silicagel column chromatography in which a developing solvent consisting ofchloroform, methanol and ammonia water in a ratio of 10:1:0.1 was used,thereby to obtain 1.0 g of a tautomer having the following formula:##STR6##

The compound so obtained also exhibited the following characteristics:

Infrared rays absorption spectra [KBr method, cm⁻¹ ] 3270, 1600, 1485,1250, 1115, 1065, 860, 755

Nuclear magnetic resonance spectra (DMSOd₆, δ value, ppm) 1.59 (q, 2H),2.24 (t, 4H), 2.28 (t, 2H), 2.83 and 3.50 (dd, 2H), 3.13 (t, 2H), 3.54(t, 4H), 4.15 (dd, 1H), 6.98 (dd, 1H), 7.03 (td, 1H), 7.35 (dd, 1H)

Examples 3 to 129

The compounds represented by the formula (Ia) were prepared in the samemanner as in Example 1 (Examples 3 to 122). The substituents in thecompounds and the melting points of the compounds are shown in Tables 1and 2.

The compounds represented by the formula (Ib) were prepared in the samemanner as in Example 2 (Examples 123 to 129). The substituents in thecompounds and the results of infrared spectrography are shown in Table3.

                                      TABLE 1                                     __________________________________________________________________________    Ex-                                                                           ample                                       Melting Point                     No. X, Y   n R.sub.1                                                                              R.sub.2           R.sub.3                                                                             (°C.)                      __________________________________________________________________________    3   H      0 H      CH.sub.3          H     188-189                           4   5-Cl   0 H      CH.sub.3          H     225-227                           5   6-Cl   0 H      CH.sub.3          H     250 (dec.)                        6   7-Cl   0 H      CH.sub.3          H     226-227                           7   H      1 H      CH(CH.sub.3).sub.2                                                                              H     135-136                           8   5-Cl   1 H      CH(CH.sub.3).sub.2                                                                              H     172-173                           9   6-Cl   1 H      CH(CH.sub.3).sub.2                                                                              H     178-179                           10  7-Cl   1 H      CH(CH.sub.3).sub.2                                                                              H     141-143                           11  5-F    1 H      CH(CH.sub.3).sub.2                                                                              H     150-151                           12  H      0 H                                                                                     ##STR7##         H     114-115                           13  5-Cl   0 H                                                                                     ##STR8##         H     160-161                           14  6-Cl   0 H                                                                                     ##STR9##         H     140-141                           15  7-Cl   0 H                                                                                     ##STR10##        H     220-222                           16  5-F    0 H                                                                                     ##STR11##        H     181-182                           17  H      0 H                                                                                     ##STR12##        CH.sub.3                                                                            230 (dec.: decomposition)         18  5-Cl   0 H                                                                                     ##STR13##        H     209-210                           19  7-Cl   0 H                                                                                     ##STR14##        H     245-247                           20  7-Cl   0 H                                                                                     ##STR15##        H     160-162                           21  7-Cl   0 H                                                                                     ##STR16##        H     178-179                           22  7-Cl   0 H                                                                                     ##STR17##        H     178-179                           23  5-Cl   0 H                                                                                     ##STR18##        H     188-189                           24  5-Cl   0 H                                                                                     ##STR19##        H     174-175                           25  H      0 H                                                                                     ##STR20##        H     240-241                           26  5-Cl   0 H                                                                                     ##STR21##        H     267 (dec.)                        27  6-Cl   0 H                                                                                     ##STR22##        H     270 (dec.)                        28  7-Cl   0 H                                                                                     ##STR23##        H     270 (dec.)                        29  5-F    0 H                                                                                     ##STR24##        H     261-264                           30  7-F    0 H                                                                                     ##STR25##        H     265-269                           31  5-CH.sub.3                                                                           0 H                                                                                     ##STR26##        H     224-226                           32  5-CH(CH.sub.3).sub.2                                                                 0 H                                                                                     ##STR27##        H     238-240                           33  H      0 CH.sub.3                                                                              ##STR28##        H     207-209                           34  7-Cl   0 H                                                                                     ##STR29##        H     270 (dec.)                        35  5-F    0 H                                                                                     ##STR30##        H     278 (dec.)                        36  7-F    0 H                                                                                     ##STR31##        H     266 (dec.)                        37  7-Cl   0 H                                                                                     ##STR32##        H     278 (dec.)                        38  7-Cl   0 H                                                                                     ##STR33##        H     280 (dec.)                        39  7-Cl   0 H                                                                                     ##STR34##        H     256-260                           40  7-Cl   0 H                                                                                     ##STR35##        H     194-197                           41  7-Cl   0 H                                                                                     ##STR36##        H     270 (dec.)                        42  7-Cl   0 H                                                                                     ##STR37##        H     227-230                           43  7-F    0 H                                                                                     ##STR38##        H     250-254                           44  7-F    0 H                                                                                     ##STR39##        H     263-266                           45  7-F    0 H                                                                                     ##STR40##        H     257-261                           46  7-F    0 H                                                                                     ##STR41##        H     270 (dec.)                        47  7-Cl   1 H                                                                                     ##STR42##        H     125-127                           48  7-Cl   2 H                                                                                     ##STR43##        H     190-194                           49  7-Cl   2 H                                                                                     ##STR44##        COCH.sub.3                                                                          168-169                           50  7-Cl   0 H      CH.sub.2CHCH.sub.2                                                                              H     178-180                           51  5-Cl   0 H                                                                                     ##STR45##        H     290 dec.                          52  6-F    2 H                                                                                     ##STR46##        H     154-156                           53  6-F    2 H                                                                                     ##STR47##        COCH.sub.3                                                                          153-154                           54  7-Cl   1 H                                                                                     ##STR48##        COCH.sub.3                                                                          180-181                           55  H      3 H      OCH(CH.sub.3).sub.2                                                                             H     108-111                           56  7-Cl   0 H                                                                                     ##STR49##        H     178-180                           57  H      2 H                                                                                     ##STR50##        H     112-114                           58  H      2 H                                                                                     ##STR51##        COCH.sub.3                                                                          173-175                           59  5-Cl   2 H                                                                                     ##STR52##        H     159-161                           60  7-Cl   2 H                                                                                     ##STR53##        H     153-155                           61  H      3 H                                                                                     ##STR54##        H     104-106                           62  H      3 H                                                                                     ##STR55##        COCH.sub.3                                                                          126-128                           63  5-Cl   3 H                                                                                     ##STR56##        H     127-128                           64  6-Cl   3 H                                                                                     ##STR57##        H     106-108                           65  6-Cl   3 H                                                                                     ##STR58##        COCH.sub.3                                                                          138-140                           66  7-Cl   3 H                                                                                     ##STR59##        H     103-104                           67  7-Cl   3 H                                                                                     ##STR60##        COCH.sub.3                                                                          180-182                           68  5,7-diCl                                                                             3 H                                                                                     ##STR61##        H     113-114                           69  5-F    3 H                                                                                     ##STR62##        H     104-106                           70  6-F    3 H                                                                                     ##STR63##        COCH.sub.3                                                                          144-146                           71  7-F    3 H                                                                                     ##STR64##        H     123-125                           72  5-CH.sub.3                                                                           3 H                                                                                     ##STR65##        H     125-127                           73  7-CH.sub.3                                                                           3 H                                                                                     ##STR66##        H     120-122                           74  5-CH(CH.sub.3).sub.2                                                                 3 H                                                                                     ##STR67##        H     141-143                           75  5-CH(CH.sub.3).sub.2                                                                 3 H                                                                                     ##STR68##        COCH.sub.3                                                                          155-157                           76  5-CH(CH.sub.3).sub.2                                                                 3 H                                                                                     ##STR69##        COCF.sub.3                                                                          85-87                             77  5-OCH.sub.3                                                                          3 H                                                                                     ##STR70##        H     normally oily                     78  6-OCH.sub.3                                                                          3 H                                                                                     ##STR71##        H     normally oily                     79  5,6-di-OCH.sub.3                                                                     3 H                                                                                     ##STR72##        H     normally oily                     80  H      3 CH.sub.3                                                                              ##STR73##        H     normally oily                     81  H      3 CH.sub.3                                                                              ##STR74##        COCH.sub.3                                                                          83-85                             82  6-Cl   3 CH.sub.3                                                                              ##STR75##        H     normally oily                     83  7-Cl   3 CH.sub.3                                                                              ##STR76##        H     normally oily                     84  7-F    3 CH.sub.3                                                                              ##STR77##        H     normally oily                     85  5,7-diCl                                                                             3 CH.sub.3                                                                              ##STR78##        H     normally oily                     86  H      3 C.sub.2 H.sub.5                                                                       ##STR79##        H     normally oily                     87  H      3 (CH.sub.2).sub.2 CH.sub.3                                                             ##STR80##        H     normally oily                     88  H      3 CH(CH.sub.3).sub.2                                                                    ##STR81##        H     normally oily                     89  H      3 (CH.sub.2).sub.4 CH.sub.3                                                             ##STR82##        H     normally oily                     90  H      3                                                                                ##STR83##                                                                            ##STR84##        H     normally oily                     91  H      3 H                                                                                     ##STR85##        H     111-113                           92  H      4 H                                                                                     ##STR86##        H     120-122                           93  H      4 H                                                                                     ##STR87##        COCH.sub.3                                                                          79-81                             94  5-Cl   4 H                                                                                     ##STR88##        H     149-151                           95  7-Cl   4 H                                                                                     ##STR89##        H     126-127                           96  H      4 CH.sub.3                                                                              ##STR90##        H     normally oily                     97  7-Cl   4 CH.sub.3                                                                              ##STR91##        H     normally oily                     98  H      2 H                                                                                     ##STR92##        H     116-118                           99  H      3 H                                                                                     ##STR93##        H     97-99                             100 H      3 H                                                                                     ##STR94##        H     93-94                             101 H      3 H                                                                                     ##STR95##        COCH.sub.3                                                                          101-103                           102 H      2 H                                                                                     ##STR96##        H     150-153                           __________________________________________________________________________

                  TABLE 2                                                         ______________________________________                                         Example No.                                                                          X, Y       R.sub.1                                                                             ##STR97##   Melting Point (°C.)               ______________________________________                                        103    H          H                                                                                    ##STR98##  113-114                                   104    5-Cl       H                                                                                    ##STR99##  167-168                                   105    6-Cl       H                                                                                    ##STR100## 150-151                                   106    7-Cl       H                                                                                    ##STR101## 156-157                                   107    5-F        H                                                                                    ##STR102## 123-124                                   108    5,7-diCl   H                                                                                    ##STR103## 167-168                                   109    5-OCH.sub.3                                                                              H                                                                                    ##STR104## 112-114                                   110    6-OCH.sub.3                                                                              H                                                                                    ##STR105## 134-135                                   111    5,6-di-OCH.sub.3                                                                         H                                                                                    ##STR106## 143-144                                   112    H          H                                                                                    ##STR107## 74-75                                     113    5-Cl       H                                                                                    ##STR108## 112-113                                   114    6-Cl       H                                                                                    ##STR109## 91-93                                     115    7-Cl       H                                                                                    ##STR110## 128-129                                   116    5-F        H                                                                                    ##STR111## 98-99                                     117    5,7-diCl   H                                                                                    ##STR112## 141-142                                   118    5-OCH.sub.3                                                                              H                                                                                    ##STR113## 96-97                                     119    6-OCH.sub.3                                                                              H                                                                                    ##STR114## 82-83                                     120    5,6-di-OCH.sub.3                                                                         H                                                                                    ##STR115## 133-134                                   121    5-Cl       H                                                                                    ##STR116## 119-120                                   122    7-Cl       H                                                                                    ##STR117## 151-153                                   ______________________________________                                    

                                      TABLE 3                                     __________________________________________________________________________                              Infrared Rays                                       Example                   Absorption Spectra                                  No.  X, Y   n R.sub.1                                                                           R.sub.2 (KBr method, cm.sup.-1)                             __________________________________________________________________________    123  7-Cl   1 H                                                                                  ##STR118##                                                                           3180, 1605, 1440 1275, 1125, 1075                   124  7-Cl   1 CH.sub.3                                                                           ##STR119##                                                                           3180, 1605, 1435 1245, 1130, 750                    125  7-Cl   2 H                                                                                  ##STR120##                                                                           3220, 1600, 1430 1250, 1120, 1090                   126  5-CH(CH.sub.3).sub.2                                                                 3 H                                                                                  ##STR121##                                                                           3150, 1610, 1490 1270, 1230, 1120                   127  6-Cl   3 H                                                                                  ##STR122##                                                                           3280, 1610, 1220 1115, 1070, 860                    128  7-Cl   2 H                                                                                  ##STR123##                                                                           3400, 1610, 1225 1115, 1065, 860                    129  H      4 H                                                                                  ##STR124##                                                                           3180, 1610, 1450 1250, 1115, 790                    __________________________________________________________________________

Pharmacological test

Groups each consisting of 9 to 10 Wistar-strained male rats, eachweighing about 200 g, were used in the test after their abstinence fromfood and water for 24 hours. Each test compound of this invention wasadministered in an amount of 50 mg/kg and a comparative medicine,"Neuer" (tradename: produced by Daiichi Pharmaceutical Co., Ltd.;effective component: centraxate) in an amount of 300 mg/kg. Each of thetest compounds was administered orally to each rat of a first group andthe comparative medicine to each rat of a second group one hour beforeoral administration of 1 ml of pure ethanol per rat. One hour later,each rat was sacrificed by exsanguination and its stomach was enucleatedand fixed with 10 ml of 70% ethanol for about 30 minutes. A 0.5%tragacanth solution was administered to each rat of a third group. Theulcer was measured for length with naked eyes, and the test groups ofrats were measured for their respective ulcer inhibition ratios incomparison with that for the third group.

Both the test compounds and the comparative medicine were each suspendedor dissolved in a 0.5% tragacanth gum saline solution for use in thetest. Table 4 shows the ulcer inhibition ratios obtained by the use ofeach of the test compounds and the comparative medicine in comparisonwith that obtained by the use of the control solution. ##EQU1##

                  TABLE 4                                                         ______________________________________                                                                 Ulcer inhibition                                     Test compounds           ratio (%)                                            ______________________________________                                        Final compound of Example 1                                                                            89.0                                                 Final compound of Example 1 (dihydrochloride)                                                          94.1                                                 Final compound of Example 1 (maleic acid salt)                                                         89.5                                                 Final compound of Example 2                                                                            93.5                                                 Final compound of Example 7                                                                            79.0                                                 Final compound of Example 59                                                                           85.0                                                 Final compound of Example 61                                                                           90.0                                                 Final compound of Example 74                                                                           93.6                                                 Final compound of Example 74 (dihydrochloride)                                                         95.3                                                 Final compound of Example 75                                                                           91.9                                                 Final compound of Example 83 (dihydrochloride)                                                         85.9                                                 Final compound of Example 92                                                                           83.4                                                 Control medicine (Neuer) 81.5                                                 ______________________________________                                    

Acute toxicity

Groups each consisting of five Wistar-strained male rats, each weighingabout 150 g, were used in the test. After each of said test compoundswas suspended in a physiological saline water, the suspension was orallyor abdominally administered to each of the test rats. The rats soadministered had been observed for 8 days to find the lethal dose (LD₅₀)with the result that the LD₅₀ of each test compound was at least 1000mg/kg when orally administered and at least 300 mg/kg when abdominallyadministered.

Industrial Applicability

From the results of the aforesaid pharmacological tests for acutetoxicity, it has been found that the compounds (Ia) and (Ib) of thisinvention and their acid addition salts have safe and remarkableantiulcerative effects with no side effects. Accordingly, when they areused for the medical treatment, prophylaxis and relapse prevention ofulcer, they will be appreciated to be enough efficacious as medicines.

What is claimed is:
 1. An indenothiazole derivative of formula:##STR125## wherein X and Y are identical with, or different from, eachother and are each hydrogen, halogen, lower alkyl having 1-6 carbonatoms or lower alkoxyl having 1-6 carbon atoms; n is an integer of from0 to 4; R₁ is hydrogen, lower alkyl having 1-6 carbon atoms or phenyl;R₂ is lower alkyl having 1-6 carbon atoms, cyclohexyl, lower alkoxylhaving 1-6 carbon atoms, alkenyl having 3-6 carbon atoms, phenyl,m-(1-piperidinylmethyl)phenoxy, phenyl substituted by a halogen atom,hydroxyl, lower alkyl having 1-6 carbon atoms, lower alkoxyl having 1-6carbon atoms or trifluoromethyl group, an heterocyclic ring selectedfrom the group consisting of pyridyl, pyridyl mono- or di-substituted byone or two lower alkyl having 1-6 carbon atoms and thiazolyl andcycloamino selected from the group consisting of morpholino, piperidino,pyrrolidino, piperazino substituted by lower alkyl having 1-6 carbonatoms and piperidino substituted by lower alkyl having 1-6 carbon atoms;R₃ is hydrogen, lower alkyl having 1-6 carbon atoms, acetyl ortrifluoromethylcarbonyl, or R₂ and R₃ are combined to form a cycloaminoselected from the group consisting of pyrrolidino group, piperidino,morpholino and piperidino di-substituted by two lower alkyl having 1-6carbon atoms.
 2. An indenothiazole derivative of formula ##STR126##wherein X and Y are identical with, or different from, each other andare each hydrogen, halogen, lower alkyl having 1-6 carbon atoms or loweralkoxyl having 1-6 carbon atoms; n is an integer of from 0 to 4; R₁ ishydrogen, lower alkyl having 1-6 carbon atoms or phenyl; and R₂ is loweralkyl having 1-6 carbon atoms, cyclohexyl, lower alkoxyl having 1-6carbon atoms, alkenyl having 3-6 carbon atoms, phenyl,m-(1-piperidinylmethyl)phenoxy group, phenyl group substituted by ahalogen atom, hydroxyl, lower alkyl having 1-6 carbon atoms, loweralkoxyl group having 1-6 carbon atoms or trifluoromethyl, anheterocyclic group selected from the group consisting of pyridyl,pyridyl mono- or di-substituted by one or two lower alkyl having 1-6carbon atoms and thiazolyl, and cycloamino selected from the groupconsisting of morpholino, piperidino, pyrrolidino, piperazinosubstituted by lower alkyl having 1-6 carbon atoms and piperidinosubstituted by lower alkyl having 1-6 carbon atoms.
 3. An indenothiazolederivative according to claim 1, in which said heterocyclic group is2-pyridyl group, 3-pyridyl group, 4-pyridyl group or 2-thiazolyl group.4. An indenothiazole derivative according to claim 1, in which saidindenothiazole derivative of the formula (Ia) is in the form of an acidaddition salt.
 5. An indenothiazole derivative according to claim 2, inwhich said indenothiazole derivative of the formula (Ib) is in the formof an acid addition salt.
 6. An indenothiazole derivative according toclaim 1, in which said halogen atom is fluorine, chlorine, bromine oriodine.